Quercetin, a plant flavonoid widely found in fruits and vegetables, is a potent antioxidant and anti- inflammatory. We recently showed that daily oral treatment with low levels of quercetin decreases oxidative stress, inflammation and prevents progression of lung disease in mice which display typical features of chronic obstructive lung disease (COPD) Our pilot studies also suggest that quercetin inhibits replication of rhinovirus, a major cause of COPD exacerbations. Finally, large epidemiological studies have suggested that a high- quercetin diet decreases the risk of COPD. Together, these data suggest that quercetin would be beneficial in the treatment of COPD. Nevertheless, key methodologic issues have not been resolved, including the dosage and frequency of supplementation, bioavailability, safety, dose-response relationship, or the appropriate biomarkers which reflect clinical outcomes in this disease. The overall goal of this application is to obtain the information necessary for large clinical trials in COPD. To accomplish this goal, we propose the following Specific Aims. 1. Determine if once-daily doses of quercetin are safe, acceptable and reach therapeutic concentrations in the plasma of patients with COPD. Using a quercetin formulation that has been generally recognized as safe by the FDA (Quercegen Pharma, Sudbury, MA), we will test the hypotheses that: 1) dietary flavonoid intake can be accurately monitored by questionnaire; and 2) daily supplementation of quercetin increases plasma quercetin levels in COPD patients; and 3) quercetin can be administered to patients with COPD of varying severity without adverse side effects. 2. Determine the effect of quercetin on oxidative stress, lung inflammation and pulmonary function in patients with COPD. We hypothesize that: 1) oxidative and inflammatory biomarkers can be safely and accurately measured in the serum and sputum of patients with COPD; 2) daily treatment with quercetin will reduce plasma and sputum markers of oxidative stress and inflammation; 3) daily treatment with quercetin will improve pulmonary function in patients with COPD. Results from these studies will provide data on the quercetin dosage and biological endpoints needed to carry out large clinical trials examining the efficacy of quercetin in COPD. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the U.S. Current treatment regimens for COPD are only partially effective, expensive, and often not adhered to by patients. In contrast to standard medications, natural products may have fewer side effects and be easy and inexpensive to use. Quercetin, a dietary chemical found in foods such as apples and onions is a natural product with anti- oxidant and anti-inflammatory properties. Our preliminary data and published studies suggest that quercetin may be useful in the treatment of COPD. The goal of this proposal is to perform a pilot study of quercetin in patients with COPD. The information gained from this study, including the correct dosage of medication and safety profile, will enable researchers to plan a large clinical trial of quercetin in the future.